Case Report Acquired Methemoglobinemia- An Overview Shibi Mary Thomas1,*, Jobin John Cherian2, Syama Priya Thampi2, Blessy George3 1Department of Pharmacy Practice, Faculty of Pharmacy, Karnataka College of Pharmacy, Bengaluru, Karnataka, INDIA. 2Pharm D Intern, Bangalore Baptist Hospital, Bengaluru, Karnataka, INDIA. 3Department of Pharmacy Practice, Chokkanahalli, Bengaluru, Karnataka, INDIA. ABSTRACT Methemoglobinemia is a life-threatening condition that can be congenital or acquired. It is characterized by the inability of haemoglobin to carry oxygen because the ferrous part of the heme molecule has been oxidized to ferric state. Acquired methemoglobinemia is due to medication or chemicals that cause the rate of methemoglobin formation to exceed its rate of reduction. We performed a search of American National library of Medicine (PubMed) with the following key word “Acquired Methemoglobinemia”. Two hundred forty-two episodes (40.1% published in year 2000 or after) were found. A retrospective case series was found. In which it describes the cases of acquired methemoglobinemia detected and the clinical circumstances under which they occurred at two tertiary care hospitals and affiliated outpatient clinics over 28 months. One hundred thirty-eight cases of acquired methemoglobinemia were detected over 28 months. There were no gender predisposition and performed over a wide range of age (Patient aged 4 days to 86 years). Signs and symptoms of acquired methemoglobinemia usually occur within 20-30 min of drug administration. One of first sign is cyanosis. Early symptoms include anxiousness and dizziness, with fatigue and confusion. The diagnosis of methemoglobinemia is based on clinical assessment when respiratory status does not explain the cyanosis that a patient has and is refractory to oxygen therapy. As management of methemoglobinemia depends on precise detection, clinicians who administer or prescribe oxidizing agent must be aware of clinical symptoms of methemoglobinemia. Methylene blue is currently the drug of choice for the management of methemoglobinemia. Key words: Methemoglobinemia, Haemoglobin, Ferrous, Ferric, Oxidation, Acquired Methemoglobinemia, Cyanosis, Anxiousness, Dizziness, Methylene Blue. Synonyms Haemoglobin M disease; Erythrocyte reductase deficiency; generalized reductase deficiency, Gibson’s syndrome. INTRODUCTION Methemoglobin is the oxidized form of concentration of organic phosphates are haemoglobin, which does not bind oxygen also significant. Local conditions in the and increases the affinity of oxygen for the lungs (relatively high pO2, low pCO2, etc.) DOI: 10.5530/ijopp.12.4.57 partially oxidized portion of haemoglobin. are associated with high affinity, so that Address for Increased levels of methemoglobin in the haemoglobin readily binds oxygen here; the correspondence: blood are secondary to congenital changes or product of this binding is oxyhaemoglobin. Prof. Shibi Mary Thomas, Assistant Professor, Faculty exposure to several drugs, chemical agents, By contrast in the microvasculature of the of Pharmacy, Department of or food items resulting in a disorder with tissue, local condition (relatively low pO , Pharmacy Practice, 2 Karnataka College of Pharmacy, 1 cyanosis. It can lead to death if not treated. high pCO2, etc.) are associated with low Bengaluru, Karnataka, INDIA. haemoglobin affinity for oxygen and oxy Phone no: +91 9164600201 Email Id: shibipractice@gmail. Normal Physiology haemoglobin readily dissociates, releasing com The principle function of haemoglobin oxygen to tissue cells. is to deliver oxygen from lungs to tissue cells, depending upon the variable affinity Haemoglobin and Methemoglobin that haemoglobin has for oxygen. This The adult haemoglobin comprises four affinity is principally dependent on the local folded polypeptide chains (two alphas and partial pressure of oxygen (pO2), but pH, two betas), each of which has a porphyrin 2 www.ijopp.org partial pressure of carbon dioxide (pCO2), heme group attached. At the centre of 270 Indian Journal of Pharmacy Practice, Vol 12, Issue 4, Oct-Dec, 2019 Thomas, et al.: Methemoglobinemia each of the four heme group is an atom of iron in Sex 2+ the ferrous (Fe ) state. These four iron atoms are No difference exists in disease occurrence of acquired the functional centres of haemoglobin molecule methemoglobinemia between males and females. because it is here that oxygen reversibly binds to form oxyhemoglobin.3 The only difference between Age haemoglobin and methemoglobin is that one or more Infants (especially premature infants) are more susceptible of the four iron atoms in methemoglobin molecule are to the development of methemoglobinemia after drug or 3+ 2+ in ferric (Fe ) state rather than ferrous (Fe ) state and toxin exposure. This is because infants have significantly 4 are therefore incapable of binding oxygen. Conversion lower levels of cytochrome b5 reductase. of iron from the ferrous to ferric state represents loss 5 of an electron, i.e. it is an oxidative process. Indian Perspective When the haemoglobin, Hgb(Fe(II))O2, is auto-oxidized • In India, methemoglobinemia is not very common, to methemoglobin, Hgb(Fe(III)), the methemoglobin, is which may be due to lack of awareness or lack of epi- recycled back to haemoglobin Hgb(Fe(II)) so that in the demiological studies on the disease. steady state the amount of intracellular methemoglobin • Groundwater is a major source of drinking water is <1%. The methemoglobin is reduced by the NADH- in rural Karnataka. Most districts, where drink- cytochrome b5-metHgb reductase. In addition, reduction ing water is supplied through bore wells, have a can be done by several alternative pathways such as high concentration of nitrates and fluorides. The NADPH-dependent MetHgb reductase and direct main cause for these high concentrations is open reduction by intracellular ascorbate and glutathione.6 sewage disposal and use of nitrogen fertilizers (Figure 1) (D Majumdar-2003, the blue baby syndrome-Indian Academy of Sciences/Resonance, October 2003. pp. Epidemiology 20-30). United States • The sanitation coverage in some districts like Gulbarga, Bijapur, Raichur and Tumkur is below 20%. Hereditary methemoglobinemia is a rare condition. This enzymatic deficiency is endemic in certain Native • Fertilizer consumption in India is concentrated in about one-third of the cultivated area. American tribes (Navajo and Athabascan Alaskans). • In India, the chemical industry is growing rapidly in International the western part, mainly in Gujarat and Maharashtra. Ahmedabad is surrounded by a large number of indus- Methemoglobinemia occurs rarely throughout the world. trial units manufacturing dyes and dye intermediates. Cytochrome b5 reductase deficiency (type Ib5R) is also Workers in these units are at high-risk of developing endemic in the Yakutsk people of Siberia. acute methemoglobinemia.7 Race • An analysis of nitrates in the groundwater in Punjab by Greenpeace revealed nitrate pollution in drinking water. The congenital form of methemoglobinemia due to The most significant potential health effects of drink- cytochrome b5 reductase deficiency (type Ib5R) is ing water contaminated with nitrate are the blue-baby endemic in certain ethnic groups. These groups include syndrome, methemoglobinemia and cancer. the Navajo, Athabascan Alaskans and the Yakutsk people • A study from three districts of West Bengal highlights in Siberia. occupational morbidity among agricultural child labour. Apart from deaths due to explosions and fire, cough- ing, sore throat, dizziness, methemoglobinemia and anemia are common effects of ingestion or inhalation of chlorate dust.8 • Congenital methemoglobinemia due to NADH-methe- moglobin reductase deficiency in three Indian families recognized in a Mumbai-based study.9 Clinical Features and Pathophysiology Symptoms are proportional to the fraction of Figure 1: NADH dependent cytochrome b5 – methemoglobin methemoglobin. A normal methemoglobin fraction is reductase system. about 1% (range, 0-3%). Indian Journal of Pharmacy Practice, Vol 12, Issue 4, Oct-Dec, 2019 271 Thomas, et al.: Methemoglobinemia At methemoglobin levels of 3-15%, a slight discoloration that are secondary to deficiency of NADH cytochrome (eg, pale, grey, blue) of the skin may be present. b5 reductase, which is encoded by the CYB5R3gene. All of them are autosomal recessive disorders. Patients with methemoglobin levels of 15-20% may be Heterozygotes have 50% enzyme activity and no cyanosis; relatively asymptomatic, apart from mild cyanosis. Signs homozygotes that have elevated methemoglobin levels and symptoms at levels of 25-50% include the following: above 1.5% have clinical cyanosis. The four types are • Headache as follows: • Dyspnea • Type I – This is the most common variant and the • Light-headedness, even syncope enzyme deficiency is limited to the erythrocytes caus- • Weakness ing cyanosis; cyanosis usually, but not always, develops 11 • Confusion during infancy. • Palpitations, chest pain • Type II – Widespread deficiency of the enzyme Methemoglobin levels of 50-70% can cause the following: occurs in various tissues, including erythrocytes, liver, fibroblasts and brain; it is associated with severe CNS • Cardiovascular - Abnormal cardiac rhythms symptoms, including encephalopathy, microcephaly, • CNS - Altered mental status; delirium, seizures, coma hypertonia, athetosis, opisthotonos, strabismus, mental • Metabolic - Profound acidosis retardation and growth retardation; cyanosis is evident at